Mcp1 Promotes Macrophage-Dependent Cyst Expansion in Autosomal Dominant Polycystic Kidney Disease.

BACKGROUND

In patients with autosomal dominant polycystic kidney disease (ADPKD), most of whom have a mutation in or , abnormally large numbers of macrophages accumulate around kidney cysts and promote their growth. Research by us and others has suggested that monocyte chemoattractant protein-1 (Mcp1) may be a signal for macrophage-mediated cyst growth.

METHODS

To define the role of Mcp1 and macrophages in promoting cyst growth, we used mice with inducible knockout of alone (single knockout) or knockout of both and (double knockout) in the murine renal tubule. Levels of RNA expression were measured in single-knockout mice and controls.

RESULTS

In single-knockout mice, upregulation of precedes macrophage infiltration. Macrophages accumulating around nascent cysts (0-2 weeks after induction) are initially proinflammatory and induce tubular cell injury with morphologic flattening, oxidative DNA damage, and proliferation-independent cystic dilation. At 2-6 weeks after induction, macrophages switch to an alternative activation phenotype and promote further cyst growth because of an additional three-fold increase in tubular cell proliferative rates. In double-knockout mice, there is a marked reduction in expression and macrophage numbers, resulting in less initial tubular cell injury, slower cyst growth, and improved renal function. Treatment of single-knockout mice with an inhibitor to the Mcp1 receptor Ccr2 partially reproduced the morphologic and functional improvement seen with knockout.

CONCLUSIONS

Mcp1 is upregulated after knockout of and promotes macrophage accumulation and cyst growth both proliferation-independent and proliferation-dependent mechanisms in this orthologous mouse model of ADPKD.